ProjectSummary While there are many public health strategies in place for reducing HIV-1 infection rates in drug users, an effectiveHIV-1vaccineremainscriticaltothiseffort.StudiesofHIV-1transmission,pathogenesis,andvaccine development are mostly conducted in macaque monkeys, although this primate model of HIV-1 infection has many limitations. In the decades since the macaque model was established, we have learned a tremendous amount about the immune response against HIV-1 and SIV.However, this hard-earned knowledgehas never beensynthesizedintoanintegrated,rationalapproachforre-evaluatingandoptimizingthenonhumanprimate modelforHIV-1infection.BytheendofthisproposedprojectwewillhaveHIV-1,oraveryminimallyengineered form, replicating in monkeys. To accomplish this goal, we present a principled approach capitalizing on the enormousknowledgebaseinthefield,andonthesubstantialgeneticdiversitypresentinanimalsheldcaptive in primate research centers. We will genotype restriction factor alleles from thousands of nonhuman primates representing several key primate species (rhesus macaques, pigtailed macaques, owl monkeys, baboons, marmosets, and squirrel monkeys) and test all discovered restriction factor alleles against HIV-1. Each discoveredallelewillbegivenanHIV-compatibilityscore,allowingsystematicandrationaldeterminationofwhich species, and which specific individuals within those species, have restriction factor genotypes that will require minimalmodificationofHIV-1.Aspartofourapproach,wewillalsoevaluateMHC,KIR,andantibodyreceptor (FcR) gene content and allelic diversity in these primate species. We will specifically optimize this model for infectionwithtransmitted/founder(T/F)HIV-1,thevariantsthataneffectivevaccineneedstorecognize.Wewill consider T/F viruses after both sexual and intravenous infection, the two main modes by which drug users acquireHIV-1infection.AmodelofpersistentHIV-1infectioninmonkeyswillopenupexcitingnewavenuesin thestudyofHIV-1pathogenesisandtransmission,andinthedevelopmentofdrugsandvaccines.